Abstract Our project represents a new collaboration of two laboratories with differing but complementary skills, with the goal of understanding plasticity of specific spinal circuits and the effects of epidural stimulation on these. The project is built on new observations and paradigms developed by both our laboratories. Although we understand increasingly more about both (a) spinal circuits at the level of molecular genetics identified developmental interneuron classes and (b) spinal plasticity in the context of spinal cord injury (SCI), these two types of information are only rarely integrated experimentally to fully leverage the power of their combination. We will use a novel paradigm which explores the combination of biological/viral, bionic and rehabilitation therapies in complete SCI in both the rat and the mouse in order to obtain the power of both approaches in analyzing spinal plasticity and pathology after SCI. In the rat model in this paradigm we already have new data showing that the combination of rehabilitation and virally derived BDNF treatment after complete SCI leads to significant gains in function as a result of this combination treatment. However, in 40% of the treated rats, after the initial high gains achieved, it was observed that a hyperreflexia developed, causing a large collapse in function. In contrast, it was observed that in rats which also receive epidural stimulation (ES) of lumbosacral spinal cord during treatment (in addition to the viral driven BDNF and rehabilitative treatments) no rats showed any such hyperreflexia. This project seeks to use this paradigm to understand plasticity of spinal circuits that support function, create hyperreflexia and collapse, and that prevent such collapse with ES. We do not yet know if there exist specific time windows for the ES efficacy in preventing collapse. The ES in some way steers the course of plasticity away from pathology in the model when applied in a timely way. Our overall Aims are to characterize the best timing of ES and to understand in detail many of the changes that result. We seek to determine if specific genetically identified circuits show plasticity, and are targets of ES, and how these circuits contribute and alter in order to support walking functions. We also seek to understand what goes awry to cause collapse of function in some animals without ES treatment. Our planned work is important and impactful because it will shed new light on circuit changes and function after SCI. It will test how identified interneuron populations and functional circuits in the spinal cord are altered. It will deepen and broaden our understanding of the actions of epidural stimulation in promoting and shaping spinal plasticity supporting walking, and identify the therapeutic targets, windows of action, and interactions of epidural stimulation with other therapies. ES is becoming a promising and broadly applicable therapy for SCI conditions, but our understanding of fundamental mechanisms of action and interaction with other therapies remains limited. This project begins to address this gap using precise physiological and genetic methods.